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HydrogelsBasedonNaturalPolymers

HydrogelsBasedonNatural Polymers

SchoolofMaterialsScienceandEngineering, BeijingInstituteofTechnology, Beijing,P.R.China

Elsevier

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Listofcontributors

HamidehAghahosseini DepartmentofChemistry,UniversityofZanjan,Zanjan,Iran

NourElhoudaBenAmmar LaboratoryofUsefulMaterialsValuation,NationalCenterof ResearchinMaterialScience(CNRSM),Soliman,Tunisia

MohamedBarbouche LaboratoryofNanomaterialsandSystemsforRenewableEnergy,Research andTechnologiesCentreofEnergy,Hammam-Lif,Tunisia

YuChen SchoolofMaterialsScienceandEngineering,BeijingInstituteofTechnology,Beijing, P.R.China

NarayanCh.Das RubberTechnologyCentre,IndianInstituteofTechnology,Kharagpur,India; SchoolofNanoscienceandTechnology,IndianInstituteofTechnology,Kharagpur,India

PoushaliDas SchoolofNanoscienceandTechnology,IndianInstituteofTechnology,Kharagpur, India

GuoxingDeng DepartmentofAppliedBiologyandChemicalTechnology,HongKong PolytechnicUniversity,HongKong

MihengDong SchoolofMaterialsScienceandEngineering,BeijingInstituteofTechnology, Beijing,P.R.China

SayanGanguly RubberTechnologyCentre,IndianInstituteofTechnology,Kharagpur,India

MohamedMohamadyGhobashy RadiationResearchofPolymerchemistrydepartment,National CenterforRadiationResearchandTechnology(NCRRT),AtomicEnergyAuthority,Cairo,Egypt

VishwajeetSampatraoGhorpade DepartmentofPharmaceutics,SchoolofPharmaceutical Sciences,SanjayGhodawatUniversity,Kolhapur,India

AhmedHichemHamzaoui LaboratoryofUsefulMaterialsValuation,NationalCenterof ResearchinMaterialScience(CNRSM),Soliman,Tunisia

MinjianHuang DepartmentofAppliedBiologyandChemicalTechnology,HongKong PolytechnicUniversity,HongKong

B.Kaczmarek FacultyofChemistry,DepartmentofChemistryofBiomaterialsandCosmetics, NicolausCopernicusUniversityinTorun,Torun,Poland

Wing-FuLai DepartmentofAppliedBiologyandChemicalTechnology,HongKongPolytechnic University,HongKong

YilinLeng SchoolofMaterialsScienceandEngineering,BeijingInstituteofTechnology,Beijing, P.R.China

RongLi ShanghaiInstituteofAppliedPhysics,ChineseAcademyofSciences,Shanghai, P.R.China

K.Nadolna FacultyofChemistry,DepartmentofChemistryofBiomaterialsandCosmetics, NicolausCopernicusUniversityinTorun,Torun,Poland

HassanNamazi ResearchLaboratoryofDendrimersandNano-Biopolymers,Facultyof Chemistry,UniversityofTabriz,Tabriz,Iran;ResearchCenterforPharmaceuticalNanotechnology (RCPN),TabrizUniversityofMedicalScience,Tabriz,Iran

A.Owczarek FacultyofChemistry,DepartmentofChemistryofBiomaterialsandCosmetics, NicolausCopernicusUniversityinTorun,Torun,Poland

JyotishkumarParameswaranpillai CenterofInnovationinDesignandEngineeringfor Manufacturing,KingMongkut’sUniversityofTechnologyNorthBangkok,Bangkok,Thailand

MalihePooresmaeil ResearchLaboratoryofDendrimersandNano-Biopolymers,Facultyof Chemistry,UniversityofTabriz,Tabriz,Iran

AliRamazani DepartmentofChemistry,UniversityofZanjan,Zanjan,Iran

SanjayMavinkereRangappa DepartmentofMechanicalandProcessEngineering,The SirindhornInternationalThai-GermanGraduateSchoolofEngineering(TGGS),KingMongkut’s UniversityofTechnologyNorthBangkok,Bangkok,Thailand

SuchartSiengchin DepartmentofMechanicalandProcessEngineering,TheSirindhorn InternationalThai-GermanGraduateSchoolofEngineering(TGGS),KingMongkut’sUniversityof TechnologyNorthBangkok,Bangkok,Thailand

Nata ˇ sa ˇ Skalko-Basnet DrugTransportandDeliveryResearchGroup,DepartmentofPharmacy, FacultyofHealthSciences,UniversityofTromsøTheArcticUniversityofNorway,Tromsø, Norway

XiaoyuSun SchoolofMaterialsScienceandEngineering,BeijingInstituteofTechnology, Beijing,P.R.China

ShuxianTang SchoolofMaterialsScienceandEngineering,BeijingInstituteofTechnology, Beijing,P.R.China

ˇ

ZeljkaVani ´ c DepartmentofPharmaceuticalTechnology,FacultyofPharmacyandBiochemistry, UniversityofZagreb,Zagreb,Croatia

SandhyaAliceVarghese DepartmentofMechanicalandProcessEngineering,TheSirindhorn InternationalThai-GermanGraduateSchoolofEngineering(TGGS),KingMongkut’sUniversityof TechnologyNorthBangkok,Bangkok,Thailand

Wing-TakWong DepartmentofAppliedBiologyandChemicalTechnology,HongKong PolytechnicUniversity,HongKong

GuozhongWu ShanghaiInstituteofAppliedPhysics,ChineseAcademyofSciences,Shanghai, P.R.China

RunyuWu DepartmentofAppliedBiologyandChemicalTechnology,HongKongPolytechnic University,HongKong

JueyingYang SchoolofMaterialsScienceandEngineering,BeijingInstituteofTechnology, Beijing,P.R.China

JingjingYuan SchoolofMaterialsScienceandEngineering,BeijingInstituteofTechnology, Beijing,P.R.China

RonnieYuan DSM(China)Limited,Shanghai,China

FeiZhang DSM(China)Limited,Shanghai,China

HongbinZhang ShanghaiJiaoTongUniversity,Shanghai,China

YingZhang SchoolofMaterialsScienceandEngineering,BeijingInstituteofTechnology, Beijing,P.R.China

LinZhao SchoolofMaterialsScienceandEngineering,BeijingInstituteofTechnology,Beijing, P.R.China

Propertiesanddevelopmentofhydrogels

SchoolofMaterialScienceandEngineering,BeijingInstituteofTechnology,Beijing,China

Hydrogelsareatypeofpolymernetworkthatcanabsorbandstorelargeamountsofwater [1].Thehydrophilicgroupsorsegmentsofthepolymernetworkcanbehydratedunder neutralconditionstoproduceagelstructure [2].Thecross-linkednetworkstructure preventsthedissolutionofthehydrophilicpolymerchainsorsegments.Hydrogelsare solid-likeandshownonflowingpropertiesasinverted.Theycanalsobedescribedbytheir fluidics [3].Ingeneral,alow-concentrationaqueoushydrophilicpolymersolutionwithno entangledstructuresexhibitsNewtonianmechanicalbehavior.Cross-linkedhydrogels possessrheologicalpropertieswithextremelyhighviscosity( . 105 Pas)andhighelasticity (shearyieldstress . 2000Pa),similartosolids.Duetotheirwaterinsolubility,hydrogels aretheresearchhotspotsofswollenpolymernetworks,aswellastheirapplicationstudies. Hydrogelshavebeenappliedtoavarietyoffields,suchasdroughtresistanceindryareas [4], masksincosmetics [5],antipyreticstickers [6],analgesicstickers [7],agriculturalfilms [8], dewpreventionagentsinconstruction [9],humiditycontrol [10],water-blockingagentsinthe petroleumindustry [11],dehydrationofcrudeoilandrefinedoil [12],dustsuppressantsin mining [13],foodpreservatives [14],thickeners [15],pharmaceuticalcarriersinmedical applications [16],tissueengineeringscaffolds [17],wounddressings [18],etc.Itisworth notingthatdifferentapplicationfieldsrequiredifferentpolymermaterials.

In1960,WichterleandLimsynthesizedacross-linkedHEMAhydrogelforthefirsttime [19].Itshighhydrophilicityandbiocompatibilityattractedgreatinterestinthebiomaterial fieldandithasbeenwidelyusedincontactlensessincethen.Themostimportantand influentialdiscoverywasthesuccessfulembeddingofcellsinanalginicacidmicrocapsule byLimandSunin1980 [20].Later,Yannasandhiscoworkerspreparedhydrogelsusing naturalpolymers,collagenandsharkcartilage,andexploredtheirapplicationsasburn wounddressings [21].Thenaturalpolymerhydrogelshavebecometheresearchhotspotfor cellembedding.Later,withtherapiddevelopmentoftissueengineering,hydrogelswere usedasthematrixforcellgrowthandcarrierofgrowthfactorstorepairandre-elevate organsofvarioustissues [22 24].Withthechangesintheapplicationpurposeand

correspondingauthor

requirement,theresearchanddevelopmentofhydrogelhaveshiftedfromtraditional hydrogelstointelligenthydrogels.

Hydrogelscanbeclassifiedbydifferentmethods.

1.Hydrogelscanbeclassifiedintonaturalhydrogelsandsynthetichydrogelsbasedon theirsources.

a.Naturalpolymers,suchascollagen,gelatin,hyaluronicacid,fibrin,sodium alginate,agarose,chitosan,dextran,cyclodextrin,etc.arefromnaturalsourceswith goodbiocompatibilityandbiodegradability [25 30].Thehydrogelspreparedwith theseabundantpolymersinherittheseexcellentpropertiesandaresensitivetothe externalenvironment.Thereforetheyhavebecometheresearchhotspotofhydrogel andarethefocusofthisbook.Inaddition,mostanimalsandplantscontainalarge numberofnaturalpolymergels.Thestudyofthestructureandpropertiesofsuch hydrogelsisalsoanimportantwaytostudythephysiologicalmechanismsof tissuesforbiomimeticapplications [31 33].

b.Synthetichydrogelsarecross-linkedpolymerspreparedbytheadditionreactionor ring-openingpolymerizationunderartificialconditions.Polyacrylicacidandits derivatives [34],polyvinylalcohol [35],polyethyleneglycolanditscopolymers [36],andpolyvinylpyrrolidone [37],etc.areusuallyusedastheskeletonsto preparesynthetichydrogels.Synthetichydrogelshavetheadvantagesofeasy industrialproductionandchemicalmodificationandpreciselycontrollable properties,yetwithpoorbiocompatibility,bioactivity,andbiodegradability,as comparedwithnaturalpolymerhydrogels.

2.Basedontheformationmechanismofthree-dimensionalnetworkstructure,hydrogels canbedividedintochemicalhydrogelsandphysicalhydrogels.

a.Chemicalhydrogelsareformedbythechemicalcross-linkingbetweenmolecules, andthiscross-linkingisirreversible.Chemicalhydrogelsusuallyhavethe advantagesofstableproperties,tunablestructures,goodmechanicalproperties,etc. [38 40]

b.Physicalhydrogelsaremainlythethree-dimensionalnetworksformedby noncovalentbonds(secondarybonds),suchaselectrostaticinteraction,hydrogen bonding,chainentanglement,andhydrophobicinteraction,betweenlinear moleculesthatformphysicalcross-linkingjoints [34,41,42] .Physicalhydrogels usuallyexhibitreversiblesol gelconversionbecauseverylowenergiesare requiredtobreakthephysicalinte ractionsbetweenthemolecules [43] .No chemicalreactionisinvolvedintheirp reparationandthepreparationconditions arerelativelymild,whichisfavorabletotheirapplicationsinthebiomedical field [44] .

3.Basedontheirdegradability,hydrogelscanbedividedintobiodegradablehydrogeland nonbiodegradablehydrogel.

a.Mostofthenaturalpolymerhydrogelsarebiodegradablehydrogels [45].Thethreedimensionalstructuresofthesehydrogelscanbedestroyedbytheactionsof microorganismsandenzymesundernaturalconditions.Thebondingbetweenthe molecularchainsandwithinthemolecularchainsisthenbrokenandthestrengthof thehydrogelisreduced.Eventually,thehydrogelisdegradedintosmallmolecules.

b.Nonbiodegradablehydrogelsareaclassofhydrogelsthatareinsensitiveto environmentalstimuliandcanmaintainstablestructural,physical,andchemical propertiesforalongtime.Mostsynthetichydrogelspreparedbychemicalcrosslinkingarenonbiodegradablehydrogels [46]

4.Basedontheirresponsivenesstoexternalstimuli,hydrogelscanbedividedinto environmentallyresponsivehydrogels(intelligenthydrogels)andenvironmentally unresponsivehydrogels(regularhydrogels).

a. Environmentallyresponsivehydrogels,alsoknownasintelligenthydrogelsorsmart hydrogels,canreversiblyrespondtoexternalstimuli.Whenahydrogelisexposed toenvironmentalstimuli,suchastemperature,pH,ionstrength,electricfield,light, stress,magneticfield,etc.,itsthree-dimensionalnetworkstructurechanges,swells orshrinks,ortransitsbetweenthedensephaseandthedilutephase,showing dramaticallyalteredshape,mechanicalandopticalproperties,etc.inresponsetothe stimuli.Thehydrogelwillautomaticallyreturntoalowersteadystateofinternal energyastheexternalstimulidisappear.

Thermo-responsivehydrogelsareatypeofhydrogelshowingtemperatureinducedvolumeshrinkingorswellingbehaviors [47,48].Ingeneral,theirvolumes canbevariedfromseveraltimestohundredsoftimesbytemperaturechanges.A thermo-responsivehydrogelcontainsbothhydrophilicandhydrophobicfunctional groupswithacertainratioinitsnetwork.Atlowtemperatures,thehydrophilic groupsonthepolymerchainformhydrogenbondswithwatermolecules.The polymer waterinteractionisstrongerthanthepolymer polymerinteraction.The hydrophilicitydominatesthestructure,andthepolymerchainisintheextended state.Astemperatureisincreased,thehydrogenbondingbetweenthepolymerand waterisgraduallyweakenedandthehydrophobicinteractionbetweenthe molecularchainsisenhanced.Attemperaturesclosetothelowercriticalsolution temperature(LCST),thehydrophobicinteractionbetweenthepolymerchainsis strongerthantheinteractionbetweenthepolymerandwater.Thehydrophobicity ofthepolymerchaindominatesthestructure.Thehydrogelshrinksandalarge amountofwaterinthehydrogelisreleased,whichiscalleddeswelling.The correspondingtemperatureiscalledthevolumephasetransitiontemperature (VPTT)ofthehydrogel.Thehydrogelcanreabsorbwaterandswellagainasthe temperaturedecreasesbelowtheVPTT,whichiscalledreswelling.Ingeneral,the

volumechangeofathermo-responsivehydrogelismostsignificantattheVPTT. Poly(N-isopropylacrylamide)hydrogelscontainingbothhydrophilicimidogroups ( NHCO )andhydrophobicisopropyl( CH(CH3)2)arethemostcommonly usedthermo-responsivehydrogels [49].

Apressure-sensitivehydrogelpossessesthestructuralcharacteristicsofa hydrogelandthermo-sensitivity.ItsstructurechangesattheLCSTunderthe hydrostaticpressure [50],causingswellingbehaviorsmainlyduetothe compressiblecavesinitsstructure.

ThepH-responsivehydrogelsexhibitvolumechangesasthepHoftheexternal environmentischanged.ApH-responsivehydrogeltypicallycontainsweakly acidicfunctionalgroups,suchas COOHand SO3H,orweaklyalkaline functionalgroups,suchas NH2 [51,52].Thesefunctionalgroupsarehighly hydrophilicintheionizedstateandlesshydrophilicintheneutralstate.Their degreesofionizationchangewithpH,whichchangesthechargedensity.Atthe criticalpH(usuallyaroundthepKa),theosmoticpressurebetweentheinsideand outsideofthehydrogelisdramaticallychanged,causingthevolumephase transition.Theswelling,shrinking,andosmoticpressurechangewithpHandion strengthofpH-responsivehydrogelsmakesthemsuitablefortargeteddrug delivery [53].

Intheearly1980s,Tanakaetal.discoveredthevolumephasetransitionofa polymerhydrogelunderthestimulationofanelectricfield,whichpromotedthe researchanddevelopmentofelectricfield-sensitivehydrogels [54].SimilartopHsensitivehydrogels,electricfield-sensitivehydrogelsareusuallycomposedof polymerelectrolytes.Thecounterionsofthechargedgroupsonthepolymer networkmigrateintheelectricfield.Theionconcentrationgradientacrossthe insideandoutsidethegelnetworkchangestheosmoticpressure,resultingin volumechangesorshapechangesofthehydrogel [55].Thereforesuchhydrogels canrespondtotheexternalelectricfieldwithshrinking,swelling,orbending behaviors [56]

Magneticfield-sensitivehydrogelispreparedbyhybridizingamagneticmaterial withhydrogel.Themagneticmaterialinthehydrogelrespondstothemagnetic fieldchangeswithchangesofparamagnetismanddiamagnetismormagneticfield rearrangement.Theforcegeneratedbysuchmovementandinteractioncauses macroscopicchangestothehydrogel [57].

Achemical-responsivehydrogelrespondstotheconcentrationchangesofa specificchemical,suchasglucose,antibody,enzyme,andDNA,withshrinking/ swellingvolumetricchangesorgel soltransition [58].Forexample,thepolymer networkcross-linkedbytheantigen antibodycanrespondtothefreeantigenin themediumwithvolumephasechangesbecausethefreeantigencompeteswiththe self-antigen(bondedonthepolymernetwork)tobindtheantibodylinkedtothe

Propertiesanddevelopmentofhydrogels7

polymernetwork.Thecompetitionchangesthecross-linkingdensityofthe network,resultinginresponsivebehaviors [59].

Photo-responsivehydrogelsareatypeofhydrogelthatundergovolumetric changes,phasechanges,orcolorchangesunderilluminationatcertainwavelengths [60].Therearemainlythreetypesofphoto-responsivemechanisms.Forthefirst photo-responsivemechanisms,thespecialphotoreceptor(s)iscompositedwitha thermo-responsivehydrogel,whichcanconvertphotoenergyintoheat,causinga localtemperaturerise.Whenthetemperaturereachesthephasetransition temperatureofthethermo-responsivehydrogel,thehydrogelexhibitsresponsive behaviors [61].Aphotothermalresponsivehydrogelhasbeenobtainedby introducingaphotosensitivechromophore,trisodiumchlorophyllinate,intoa thermo-responsivehydrogel [62].Thesecondphoto-responsivemechanismtakes advantageofthephotolysisofphoto-sensitivemoleculesintoions [63].Forthe thirdphoto-responsivemechanism,chromophoresareaddedintothehydrogel networkthatundergoeschangesinphysicalandchemicalpropertiesunder illumination.Thespaceorgeometryofthepolymerchainwithchromophoresis thenchanged,causingswellingorshrinkageofthehydrogel [64].Thephotothermal conversionefficiencycanbeimprovedbyreplacingtheinfraredlightandvisible lightwithhigh-energylaserordopingnanoparticles,suchascarbonnanotube [65], graphene [66],etc.,intothehydrogel.Suchstrategiescanalsopromotetheresponse rateorremotelycontrolthestimuli-responsesofhydrogels.

Multiresponsivehydrogelsarehydrogelsthatrespondtotwoormoreexternal stimuli.Thereareavarietyofmultiresponsivehydrogels,mainlyincludingpH/ temperaturedual-sensitivehydrogels [67],light/temperaturedual-sensitive hydrogels [68],andlight/pHdual-sensitivehydrogels [69].Multiresponsive hydrogelscanbepreparedwithcopolymerstructures [70],doublenetworks [71], andcore shellstructures [72].

Theuniqueintelligentresponsivepropertiesoftheenvironmentallyresponsive hydrogelsrenderthembroadapplicationprospects,suchassensors [73],artificial muscles [74],chemicalmechanicaldevices [56],chemicalstorage [75],molecular separations [76],enzymeimmobilization [77],tissueengineering [78],drug delivery [53],dimmingmaterials [79],andothersmartmaterials.The conventionalhydrogeldrugcarriersdeliverdrugsbytheosmoticactionofthe drugmoleculesandthedecompositionofthehydrogelmatrices.The environmentallyresponsivehydrogelscanbeusedtodeliverdrugsbyavarietyof intelligentregulationmeans.Hydrogelsareoftenusedforcellcultureduetotheir similaritytotissuestructures.Thedynamicresponsivecharacteristicsof environmentallyresponsivehydrogelsfacilitatetheinsituchangesinthehydrogel matrix,suchasadhesionandmechanicalstrength,todynamicallyregulatethe growthenvironmentofcells [48].

b. Environmentallyunresponsivehydrogels

Hydrogelswithstablestructuresandphysicalandchemicalpropertiesunder differentenvironmentalconditions [80],forexample,environmental unresponsiveness,areneededforsomespecialapplications.Forexample,agaroseis highlyhydrophilicandbiodegradable,buthasalmostnochargedgroups.Its hydrogelisrarelydesaturatedbyoradsorbedbysensitivebiomacromolecules,and thusitisoftenusedasasupportmatrixforimmunoelectrophoresisorgelation [81].

5.Basedontheirsize,hydrogelscanbeclassifiedintobulkhydrogelsand microhydrogels.

a.Bulkhydrogelsarethelargepiecesofhydrogelswithcertainshapesandsizes [82], usuallyintheformsoflow-strengthjellywithcertainfluidityandviscosity.They areusuallyusedinbeautysalonsandfoodprocessing [83].Bulkhydrogelswith certainstrengthsandthicknessescanalsobeusedintissueengineering,food processing,films,coatingsoninertbiosensors [84],andantibacterialcoatings [85].

Despiteitsexcellentpropertiesandwideapplications,theprocessingandshapingof thissoftandlow-strengthaqueousmaterialremainchallenginganditsapplicationsin somespecialfieldsarelimited.Thereforeeffortshavebeenmadetoimprovethe strengthofbulkhydrogelsbyintroducingareinforcingphaseintothematrix,which givesthehydrogelnewphysicalandchemicalproperties [86].Inparticular, nanocompositehydrogelspreparedbydispersinginorganic nanoparticlesintohydrogel matricescanfusetherigidity,dimensionalstability,andthermalstabilityofthe nanomaterialwiththesoftnessandwettabilityofthehydrogel,producingbetter physicalandmechanicalpropertiesandthermalstability [87].Theenhanced performancesofthehydrogelscanbeexplainedbythepermeationtheory,nanoparticle/ polymercross-linkedstructure,orpolymer/nanoparticleintercalationstructure [88].

b.Microhydrogelsareindividualandsmallerhydrogels [89],ascomparedwiththe bulkhydrogel.Amongthem,microhydrogelsofnanometerscalearethefocusand hotspotofresearch [90].Thequantumeffectandsurfaceeffectproducedbythe smallsizesandlargespecificsurfaceareasofthenano-scalemicrohydrogelsrender themexcellentperformancesinmechanics,electricity,optics,magnetism,and catalysisapplications [91].

6.Basedontheirfunctionsinpracticalapplications,hydrogelscanbedividedintoinsitu hydrogels,molecularlyimprintedhydrogels,nanohydrogels,andporoushydrogels.

a. Insituhydrogels

Apolymerundergoesreversiblechangesofstateortransformationof conformationunderphysiologicalconditionswithchangesintheexternal environment,suchastemperature,pH,ionicstrength,etc.,whichcausesthephase transitionfromthesolutiontothesemisolidgel,forminganinsituhydrogel [92]. Comparedwithconventionalhydrogels,theuniquesol geltransitionofinsitu hydrogelendowsitgreatadvantagesindrugdelivery,suchaseasypreparation, easyoperation,strongaffinitywithdrugsandmucosaltissues,andlongdrug

retentiontime [93].Theinsituhydrogeldrug-deliverysystemshavebecomea researchhotspotinpharmacy.Thedrugembeddedinaninsituhydrogelcarriercan avoiddigestioninthegastrointestinaltractandeliminationintheliverduring mucosaladministration,andthusexhibitsloweffectivedoseandhigh bioavailability [94].Inaddition,thephysicalandchemicalpropertiesandthestate ofthedruginthebodyaretunableaccordingtoenvironmentchangestoachieve timelyandeffectivetherapeuticeffects.Thestrongaffinityofinsituhydrogelto mucosaltissues,longdrugretentiontime,sustainedreleaseorcontrolledrelease, goodtissuecompatibility,andeasyoperationcanreducethefrequencyofdrug administrationandimprovethequalityoflifeofpatients.Inaddition,theinsitu hydrogelcarrieddrugscanbeadministeredbyvariousroutes,suchasocular,nasal, transdermal,rectal,andinjection [95].Insituhydrogelscanalsobeusedfor targeteddrugdeliveries [96],wholebodyapplication [97],macromoleculardrugs [98],celltissues [99],hydrophilicdrugs [100],hydrophobicdrugs [101],etc.The hydrogelscanbetemperature-sensitive,ionicstrength-sensitive,orpH-sensitive.

b. Molecularlyimprintedhydrogels

Thehydrogelspreparedbymolecularimprintingexhibithighbindingabilitiesto thetemplatemolecules,andthustheycanrecognize,bind,orreleasespecific moleculesautomatically [102].Biologicalmacromolecules,suchasproteins [103], peptides [104],nucleotides [105],glucose [106],etc.,havebeenusedastemplates.

Thecombinationofmolecularimprintingwithsmarthydrogelcannotonly improvethebindingofahydrogelnetworktospecificmolecules,butalsocanswitch thememoryofahydrogelofaspecificmoleculebychangingtheexternal environment,realizingautomaticbinding andreleasingofthemolecule.Meanwhile, theconcentrationchangesofaspecificmoleculeinthemediumcanalsostimulatethe hydrogeltoswellorshrink,whichcanbeusedforcontrolledreleaseoftheembedded substance [107].Molecularlyimprintedsmarthydrogelscansenseandrespondto specificmolecules,controltheon/offswitchofthememoryofthesemoleculesbased ontheexternalstimulationsignals,and thushavegreatapplicationpotentialin biosensors [108],controlleddrugrelease [109],andimmunoassays [110]

c. Nanohydrogels

Nanohydrogelsarehighlycross-linkednano-scalehydrogelspreparedbychemical orphysicalmethods.Theycanbeusedtocarrytherapeuticcompoundswith excellentabilitytopreventprematureleakageofthetherapeuticagentand sustainablyreleasetheagent [111].Nanohydrogelscanbeabsorbedbycellsandthus theyareeffectivecarriersfortheintracellulardeliveryoftherapeuticagents [112]. Nanohydrogelsretaintheirpayloadintheextracellularenvironmentandaretriggered toreleasetheloadedagentunderthestimulationofoneormoreintracellulartriggers oncetheyareinternalizedbythetargetcells,givinggoodtherapeuticeffects.

Nanohydrogelscanbeadministeredintravenouslytoareasthatarenoteasily accessible.Theseexcellentpropertiesofnanohydrogelshaverenderedthemgreat

applicationpotentialsfortheencapsulationandsmartdeliveryoftherapeuticagents [113].However,evidencesforthedrugreleasefromnanohydrogelsinvivoor intracellularlyarestilllacking.Thein-depthunderstandingoftheiraction mechanismincellsisthekeytotheirapplication.Inaddition,thereareonlyafew reportsoftheirlong-termaccumulationanddegradation,andmorestudiesofthe invivobehaviorsofnanohydrogelsareneededbeforeanyclinicaltrials.Further studiesontheircytotoxicity,immunogenicity,pharmacokinetics,andinvivo therapeuticeffectsarestillneededbeforeapplicationofthetheoreticalstudyresults.

d. Poroushydrogels

Theapplicationpotentialsofahydrogelcanbeevaluatedwithaseriesof parameters,suchasswellingrate,swellingratio,andmechanicalstrength.The hydrogelssynthesizedbymostmethodsarenonporousorporousyetwithlow porosities,andlowswellingratesevenwithhighswellingratios,whichgreatly limitstheirapplicationsindrugdeliveryandtissueengineering.Thenumerous poresintheporoushydrogelprovidealargespecificsurfaceareawheremore hydrophilicgroupscanquicklycontactwater,which,alongwiththecapillaryaction oftheporousstructure,greatlyimprovesthewaterabsorptionrateofthehydrogel [8].Theporousstructureofahydrogelcanbetubedtoshortenthetimetoreachthe swellingequilibriumbyadjustingtheprocessingparameters,suchasthedosageof cross-linkingagent,pore-formingmethod,andthedosageofporogen [114].The environmentallyresponsiveporoushydrogelsusuallyexhibitquickerresponsesand bettersensitivity [115].However,extremelyhighporositiescansignificantly weakentheoverallmechanicalstrengthofthehydrogel.Poroushydrogelshave beenpreparedbythefreeze-dryingmethod [116],phaseseparationmethod [117], templatemethod [118],porogenmethod [119],andfoamingmethod [120].

Thestudyofhydrogelshasaverylonghistoryandimprovingtheir environmentalresponseshasbecomeanimportantresearchdirectiontopromote theirapplication [121].However,atpresent,theresponsetimeofmosthydrogelsis stillverylong,andthesizeselectivityislow.Inaddition,themechanicalproperties ofhydrogelneedtobefurtherimproved.Naturalpolymermaterialshavebecomea hotspotforthepreparationofmultifunctionalhydrogelsduetotheirgood biocompatibility,biodegradability,andmodifiability.Thisbookwillalsodiscuss progressintheresearchandapplicationofnaturalpolymerhydrogelmaterials,as wellastheexistingchallengesandwaystomakeimprovements.

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CHAPTER XXIV.

THE REASON AND END OF DIVINE PUNISHMENTS.

Now that is in our power, of which equally with its opposite we are masters,—as, say, to philosophize or not, to believe or disbelieve. In consequence, then, of our being equally masters of each of the opposites, what depends on us is found possible. Now the commandments may be done or not done by us, who, as is reasonable, are liable to praise and blame. And those, again, who are punished on account of sins committed by them, are punished for them alone; for what is done is past, and what is done can never be undone. The sins committed before faith are accordingly forgiven by the Lord, not that they may be undone, but as if they had not been done. “But not all,” says Basilides, “but only sins involuntary and in ignorance, are forgiven;” as would be the case were it a man, and not God, that conferred such a boon. To such an one Scripture says, “Thou thoughtest that I would be like thee.”[662] But if we are punished for voluntary sins, we are punished not that the sins which are done may be undone, but because they were done. But punishment does not avail to him who has sinned, to undo his sin, but that he may sin no more, and that no one else fall into the like. Therefore the good God corrects for these three causes: First, that he who is corrected may become better than his former self; then that those who are capable of being saved by examples may be driven back, being admonished; and thirdly, that he who is injured may not be readily despised, and be apt to receive injury. And there are two methods of correction—the instructive and the punitive, which we have called the disciplinary. It ought to be known, then, that those who fall into sin after baptism[663] are those who are subjected to discipline; for the deeds done before are remitted, and those done after are purged. It is in reference to the unbelieving that it is said, “that they are reckoned as the chaff which the wind drives from the face of the earth, and the drop which falls from a vessel.”[664]

CHAPTER XXV.

TRUE PERFECTION CONSISTS IN THE KNOWLEDGE AND LOVE OF GOD.

“Happy he who possesses the culture of knowledge, and is not moved to the injury of the citizens or to wrong actions, but contemplates the undecaying order of immortal nature, how and in what way and manner it subsists. To such the practice of base deeds attaches not.” Rightly, then, Plato says, “that the man who devotes himself to the contemplation of ideas will live as a god among men; now the mind is the place of ideas, and God is mind.” He says that he who contemplates the unseen God lives as a god among men. And in the Sophist, Socrates calls the stranger of Elea, who was a dialectician, “god:” “Such are the gods who, like stranger guests, frequent cities. For when the soul, rising above the sphere of generation, is by itself apart, and dwells amidst ideas,” like the Coryphæus in Theætetus, now become as an angel, it will be with Christ, being rapt in contemplation, ever keeping in view the will of God; in reality

“Alone wise, while these flit like shadows.”[665]

“For the dead bury their dead.” Whence Jeremiah says: “I will fill it with the earth-born dead whom mine anger has smitten.”[666]

God, then, being not a subject for demonstration, cannot be the object of science. But the Son is wisdom, and knowledge, and truth, and all else that has affinity thereto. He is also susceptible of demonstration and of description. And all the powers of the Spirit, becoming collectively one thing, terminate in the same point—that is, in the Son. But He is incapable of being declared, in respect of the idea of each one of His powers. And the Son is neither simply one thing as one thing, nor many things as parts, but one thing as all things; whence also He is all things. For He is the circle of all powers rolled and united into one unity. Wherefore the Word is called the Alpha and the Omega, of whom alone the end becomes

beginning, and ends again at the original beginning without any break. Wherefore also to believe in Him, and by Him, is to become a unit, being indissolubly united in Him; and to disbelieve is to be separated, disjoined, divided.

“Wherefore thus saith the Lord, Every alien son is uncircumcised in heart, and uncircumcised in flesh” (that is, unclean in body and soul): “there shall not enter one of the strangers into the midst of the house of Israel, but the Levites.”[667] He calls those that would not believe, but would disbelieve, strangers. Only those who live purely being true priests of God. Wherefore, of all the circumcised tribes, those anointed to be high priests, and kings, and prophets, were reckoned more holy. Whence He commands them not to touch dead bodies, or approach the dead; not that the body was polluted, but that sin and disobedience were incarnate, and embodied, and dead, and therefore abominable. It was only, then, when a father and mother, a son and daughter died, that the priest was allowed to enter, because these were related only by flesh and seed, to whom the priest was indebted for the immediate cause of his entrance into life. And they purify themselves seven days, the period in which Creation was consummated. For on the seventh day the rest is celebrated; and on the eighth he brings a propitiation, as is written in Ezekiel, according to which propitiation the promise is to be received.[668] And the perfect propitiation, I take it, is that propitious faith in the gospel which is by the law and the prophets, and the purity which shows itself in universal obedience, with the abandonment of the things of the world; in order to that grateful surrender of the tabernacle, which results from the enjoyment of the soul. Whether, then, the time be that which through the seven periods enumerated returns to the chiefest rest,[669] or the seven heavens, which some reckon one above the other; or whether also the fixed sphere which borders on the intellectual world be called the eighth, the expression denotes that the Gnostic ought to rise out of the sphere of creation and of sin. After these seven days, sacrifices are offered for sins. For there is still fear of change, and it touches

the seventh circle. The righteous Job says: “Naked came I out of my mother’s womb, and naked shall I return there;”[670] not naked of possessions, for that were a trivial and common thing; but, as a just man, he departs naked of evil and sin, and of the unsightly shape which follows those who have led bad lives. For this was what was said, “Unless ye be converted, and become as children,”[671] pure in flesh, holy in soul by abstinence from evil deeds; showing that He would have us to be such as also He generated us from our mother —the water.[672] For the intent of one generation succeeding another is to immortalize by progress. “But the lamp of the wicked shall be put out.”[673] That purity in body and soul which the Gnostic partakes of, the all-wise Moses indicated, by employing repetition in describing the incorruptibility of body and of soul in the person of Rebecca, thus: “Now the virgin was fair, and man had not known her.”[674] And Rebecca, interpreted, means “glory of God;” and the glory of God is immortality. This is in reality righteousness, not to desire other things, but to be entirely the consecrated temple of the Lord. Righteousness is peace of life and a well-conditioned state, to which the Lord dismissed her when He said, “Depart into peace.”[675] For Salem is, by interpretation, peace; of which our Saviour is enrolled King, as Moses says, Melchizedek king of Salem, priest of the most high God, who gave bread and wine, furnishing consecrated food for a type of the Eucharist. And Melchizedek is interpreted “righteous king;” and the name is a synonym for righteousness and peace. Basilides, however, supposes that Righteousness and her daughter Peace dwell stationed in the eighth sphere.

But we must pass from physics to ethics, which are clearer; for the discourse concerning these will follow after the treatise in hand. The Saviour Himself, then, plainly initiates us into the mysteries, according to the words of the tragedy:[676]

“Seeing those who see, he also gives the orgies.”

And if you ask,

“These orgies, what is their nature?”

You will hear again:

“It is forbidden to mortals uninitiated in the Bacchic rites to know.”

And if any one will inquire curiously what they are, let him hear:

“It is not lawful for thee to hear, but they are worth knowing; The rites of the God detest him who practises impiety.”

Now God, who is without beginning, is the perfect beginning of the universe, and the producer of the beginning. As, then, He is being, He is the first principle of the department of action, as He is good, of morals; as He is mind, on the other hand, He is the first principle of reasoning and of judgment. Whence also He alone is Teacher, who is the only Son of the Most High Father, the Instructor of men.

CHAPTER XXVI.

HOW THE PERFECT MAN TREATS THE BODY AND THE THINGS OF THE WORLD.

Those, then, who run down created existence and vilify the body are wrong; not considering that the frame of man was formed erect for the contemplation of heaven, and that the organization of the senses tends to knowledge; and that the members and parts are arranged for good, not for pleasure. Whence this abode becomes receptive of the soul which is most precious to God; and is dignified with the Holy Spirit through the sanctification of soul and body, perfected with the perfection of the Saviour. And the succession of the three virtues is found in the Gnostic, who morally, physically, and logically occupies himself with God. For wisdom is the knowledge of things divine and human; and righteousness is the concord of the parts of the soul; and holiness is the service of God. But if one were to say that he disparaged the flesh, and generation on account of it, by quoting Isaiah, who says, “All flesh is grass, and all the glory of man as the flower of grass: the grass is withered, and the flower has fallen; but the word of the Lord endureth for ever;”[677] let him hear the Spirit interpreting the matter in question by Jeremiah, “And I scattered them like dry sticks, that are made to fly by the wind into the desert. This is the lot and portion of your disobedience, saith the Lord. As thou hast forgotten me, and hast trusted in lies, so will I discover thy hinder parts to thy face; and thy disgrace shall be seen, thy adultery, and thy neighing,” and so on.[678] For “the flower of grass,” and “walking after the flesh,” and “being carnal,” according to the apostle, are those who are in their sins. The soul of man is confessedly the better part of man, and the body the inferior. But neither is the soul good by nature, nor, on the other hand, is the body bad by nature. Nor is that which is not good straightway bad. For there are things which occupy a middle place, and among them are things to be preferred, and things to be rejected. The constitution of man, then, which has its place among things of

sense, was necessarily composed of things diverse, but not opposite —body and soul.

Always therefore the good actions, as better, attach to the better and ruling spirit; and voluptuous and sinful actions are attributed to the worse, the sinful one.

Now the soul of the wise man and Gnostic, as sojourning in the body, conducts itself towards it gravely and respectfully, not with inordinate affections, as about to leave the tabernacle if the time of departure summon. “I am a stranger in the earth, and a sojourner with you,” it is said.[679] And hence Basilides says, that he apprehends that the election are strangers to the world, being supramundane by nature. But this is not the case. For all things are of one God. And no one is a stranger to the world by nature, their essence being one, and God one. But the elect man dwells as a sojourner, knowing all things to be possessed and disposed of; and he makes use of the things which the Pythagoreans make out to be the threefold good things. The body, too, as one sent on a distant pilgrimage, uses inns and dwellings by the way, having care of the things of the world, of the places where he halts; but leaving his dwelling-place and property without excessive emotion; readily following him that leads him away from life; by no means and on no occasion turning back; giving thanks for his sojourn, and blessing [God] for his departure, embracing the mansion that is in heaven. “For we know, that, if the earthly house of our tabernacle be dissolved, we have a building of God, an house not made with hands, eternal in the heavens. For we that are in this tabernacle do groan, desiring to be clothed upon with our house which is from heaven: if so be that being clothed we shall not be found naked. For we walk by faith, not by sight,”[680] as the apostle says; “and we are willing rather to be absent from the body, and present with God.” The rather is in comparison. And comparison obtains in the case of things that fall under resemblance; as the more valiant man is more valiant among the valiant, and most valiant among cowards. Whence he adds, “Wherefore we strive, whether present or absent, to be

accepted with Him,”[681] that is, God, whose work and creation are all things, both the world and things supramundane. I admire Epicharmus, who clearly says:

“Endowed with pious mind, you will not, in dying, Suffer aught evil. The spirit will dwell in heaven above;” and the minstrel[682] who sings:

“The souls of the wicked flit about below the skies on earth, In murderous pains beneath inevitable yokes of evils; But those of the pious dwell in the heavens, Hymning in songs the Great, the Blessed One.”

The soul is not then sent down from heaven to what is worse. For God works all things up to what is better. But the soul which has chosen the best life—the life that is from God and righteousness— exchanges earth for heaven. With reason therefore, Job, who had attained to knowledge, said, “Now I know that Thou canst do all things; and nothing is impossible to Thee. For who tells me of what I know not, great and wonderful things with which I was unacquainted? And I felt myself vile, considering myself to be earth and ashes.”[683] For he who, being in a state of ignorance, is sinful, “is earth and ashes;” while he who is in a state of knowledge, being assimilated as far as possible to God, is already spiritual, and so elect. And that Scripture calls the senseless and disobedient “earth,” will be made clear by Jeremiah the prophet, saying, in reference to Joachim and his brethren, “Earth, earth, hear the word of the Lord; Write this man, as man excommunicated.”[684] And another prophet says again, “Hear, O heaven; and give ear, O earth,”[685] calling understanding “ear,” and the soul of the Gnostic, that of the man who has applied himself to the contemplation of heaven and divine things, and in this way has become an Israelite, “heaven.” For again he calls him who has made ignorance and hardness of heart his choice, “earth.” And the expression “give ear” he derives from the “organs of hearing,” “the ears,” attributing carnal things to those

who cleave to the things of sense. Such are they of whom Micah the prophet says, “Hear the word of the Lord, ye peoples who dwell with pangs.”[686] And Abraham said, “By no means. The Lord is He who judgeth the earth;”[687] “since he that believeth not, is,” according to the utterance of the Saviour, “condemned already.”[688] And there is written in the Kings[689] the judgment and sentence of the Lord, which stands thus: “The Lord hears the righteous, but the wicked He saveth not, because they do not desire to know God.” For the Almighty will not accomplish what is absurd. What do the heresies say to this utterance, seeing Scripture proclaims the Almighty God to be good, and not the author of evil and wrong, if indeed ignorance arises from one not knowing? But God does nothing absurd. “For this God,” it is said, “is our God, and there is none to save besides Him.”[690] “For there is no unrighteousness with God,”[691] according to the apostle. And clearly yet the prophet teaches the will of God, and the gnostic proficiency, in these words: “And now, Israel, what doth the Lord God require of thee, but to fear the Lord thy God, and walk in all His ways, and love Him, and serve Him alone?”[692] He asks of thee, who hast the power of choosing salvation. What is it, then, that the Pythagoreans mean when they bid us “pray with the voice?” As seems to me, not that they thought the Divinity could not hear those who speak silently, but because they wished prayers to be right, which no one would be ashamed to make in the knowledge of many. We shall, however, treat of prayer in due course by and by. But we ought to have works that cry aloud, as becoming “those who walk in the day.”[693] “Let thy works shine,”[694] and behold a man and his works before his face. “For behold God and His works.”[695] For the gnostic must, as far as is possible, imitate God. And the poets call the elect in their pages godlike and gods, and equal to the gods, and equal in sagacity to Zeus, and having counsels like the gods, and resembling the gods,—nibbling, as seems to me, at the expression, “in the image and likeness.”[696]

Euripides accordingly says, “Golden wings are round my back, and I am shod with the winged sandals of the Sirens; and I shall go aloft into the wide ether, to hold converse with Zeus.”

But I shall pray the Spirit of Christ to wing me to my Jerusalem. For the Stoics say that heaven is properly a city, but places here on earth are not cities; for they are called so, but are not. For a city is an important thing, and the people a decorous body, and a multitude of men regulated by law as the church by the word—a city on earth impregnable—free from tyranny; a product of the divine will on earth as in heaven. Images of this city the poets create with their pen. For the Hyperboreans, and the Arimaspian cities, and the Elysian plains, are commonwealths of just men. And we know Plato’s city placed as a pattern in heaven.

BOOK V. CHAPTER I.

ON FAITH.

f the gnostic so much has been cursorily, as it were, written. We proceed now to the sequel, and must again contemplate faith; for there are some that draw the distinction, that faith has reference to the Son, and knowledge to the Spirit. But it has escaped their notice that, in order to believe truly in the Son, we must believe that He is the Son, and that He came, and how, and for what, and respecting His passion; and we must know who is the Son of God. Now neither is knowledge without faith, nor faith without knowledge. Nor is the Father without the Son; for the Son is with the Father. And the Son is the true teacher respecting the Father; and that we may believe in the Son, we must know the Father, with whom also is the Son. Again, in order that we may know the Father, we must believe in the Son, that it is the Son of God who teaches; for from faith to knowledge by the Son is the Father. And the knowledge of the Son and Father, which is according to the gnostic rule—that which in reality is gnostic—is the attainment and comprehension of the truth by the truth.

We, then, are those who are believers in what is not believed, and who are gnostics as to what is unknown; that is, gnostics as to what is unknown and disbelieved by all, but believed and known by a few; and gnostics, not describing actions by speech, but gnostics in the exercise of contemplation. Happy is he who speaks in the ears of the hearing. Now Faith is the ear of the soul. And such the Lord intimates faith to be, when He says, “He that hath ears to hear, let him hear;”[697] so that by believing he may comprehend what He

says, as He says it. Homer, too, the oldest of the poets, using the word “hear” instead of “perceive”—the specific for the generic term —writes:

“Him most they heard.”[698]

For, in fine, the agreement and harmony of the faith of both[699] contribute to one end—salvation. We have in the apostle an unerring witness: “For I desire to see you, that I may impart unto you some spiritual gift, in order that ye may be strengthened; that is, that I may be comforted in you, by the mutual faith of you and me.”[700] And further on again he adds, “The righteousness of God is revealed from faith to faith.”[701] The apostle, then, manifestly announces a double faith, or rather one which admits of growth and perfection; for the common faith lies beneath as a foundation. To those, therefore, who desire to be healed, and are moved by faith, He added, “Thy faith hath saved thee.”[702] But that which is excellently built upon is consummated in the believer, and is again perfected by the faith which results from instruction and the word, in order to the performance of the commandments. Such were the apostles, in whose case it is said that “faith removed mountains and transplanted trees.”[703] Whence, perceiving the greatness of its power, they asked “that faith might be added to them;”[704] a faith which salutarily bites the soil “like a grain of mustard,” and grows magnificently in it, to such a degree that the reasons of things sublime rest on it. For if one by nature knows God, as Basilides thinks, who calls intelligence of a superior order at once faith and kingship, and a creation worthy of the essence of the Creator; and explains that near Him exists not power, but essence and nature and substance; and says that faith is not the rational assent of the soul exercising free-will, but an undefined beauty, belonging immediately to the creature;—the precepts both of the Old and of the New Testament are, then, superfluous, if one is saved by nature, as Valentinus would have it, and is a believer and an elect man by nature, as Basilides thinks; and nature would have been able, one

time or other, to have shone forth, apart from the Saviour’s appearance. But were they to say that the visit of the Saviour was necessary, then the properties of nature are gone from them, the elect being saved by instruction, and purification, and the doing of good works. Abraham, accordingly, who through hearing believed the voice, which promised under the oak in Mamre, “I will give this land to thee, and to thy seed,” was either elect or not. But if he was not, how did he straightway believe, as it were naturally? And if he was elect, their hypothesis is done away with, inasmuch as even previous to the coming of the Lord an election was found, and that saved: “For it was reckoned to him for righteousness.”[705] For if any one, following Marcion, should dare to say that the Creator (Δημιουργόν) saved the man that believed on him, even before the advent of the Lord, (the election being saved with their own proper salvation); the power of the good Being will be eclipsed; inasmuch as late only, and subsequent to the Creator spoken of by them in words of good omen, it made the attempt to save, and by his instruction, and in imitation of him. But if, being such, the good Being save, according to them; neither is it his own that he saves, nor is it with the consent of him who formed the creation that he essays salvation, but by force or fraud. And how can he any more be good, acting thus, and being posterior? But if the locality is different, and the dwelling-place of the Omnipotent is remote from the dwelling-place of the good God; yet the will of him who saves, having been the first to begin, is not inferior to that of the good God. From what has been previously proved, those who believe not are proved senseless: “For their paths are perverted, and they know not peace,” saith the prophet.[706] “But foolish and unlearned questions” the divine Paul exhorted to “avoid, because they gender strifes.”[707] And Æschylus exclaims:

“In what profits not, labour not in vain.”

For that investigation, which accords with faith, which builds, on the foundation of faith, the august knowledge of the truth, we know to be the best. Now we know that neither things which are clear are

made subjects of investigation, such as if it is day, while it is day; nor things unknown, and never destined to become clear, as whether the stars are even or odd in number; nor things convertible; and those are so which can be said equally by those who take the opposite side, as if what is in the womb is a living creature or not. A fourth mode is, when, from either side of those, there is advanced an unanswerable and irrefragable argument. If, then, the ground of inquiry, according to all of these modes, is removed, faith is established. For we advance to them the unanswerable consideration, that it is God who speaks and comes to our help in writing, respecting each one of the points regarding which I investigate. Who, then, is so impious as to disbelieve God, and to demand proofs from God as from men? Again, some questions demand the evidence of the senses, as if one were to ask whether the fire be warm, or the snow white; and some admonition and rebuke, as the question if you ought to honour your parents. And there are those that deserve punishment, as to ask proofs of the existence of Providence. There being then a Providence, it were impious to think that the whole of prophecy and the economy in reference to a Saviour did not take place in accordance with Providence. And perchance one should not even attempt to demonstrate such points, the divine Providence being evident from the sight of all its skilful and wise works which are seen, some of which take place in order, and some appear in order. And He who communicated to us being and life, has communicated to us also reason, wishing us to live rationally and rightly. For the Word of the Father of the universe is not the uttered word (λόγος προφορικός), but the wisdom and most manifest kindness of God, and His power too, which is almighty and truly divine, and not incapable of being conceived by those who do not confess—the all-potent will. But since some are unbelieving, and some are disputatious, all do not attain to the perfection of the good. For neither is it possible to attain it without the exercise of free choice; nor does the whole depend on our own purpose; as, for example, what is destined to happen. “For by grace we are saved:” not, indeed, without good works; but we must, by being formed for what is good, acquire an

inclination for it. And we must possess the healthy mind which is fixed on the pursuit of the good; in order to which we have the greatest need of divine grace, and of right teaching, and of holy susceptibility, and of the drawing of the Father to Him. For, bound in this earthly body, we apprehend the objects of sense by means of the body; but we grasp intellectual objects by means of the logical faculty itself. But if one expect to apprehend all things by the senses, he has fallen far from the truth. Spiritually, therefore, the apostle writes respecting the knowledge of God, “For now we see as through a glass, but then face to face.”[708] For the vision of the truth is given but to few. Accordingly, Plato says in the Epinomis, “I do not say that it is possible for all to be blessed and happy; only a few. Whilst we live, I pronounce this to be the case. But there is a good hope that after death I shall attain all.” To the same effect is what we find in Moses: “No man shall see my face, and live.”[709] For it is evident that no one during the period of life has been able to apprehend God clearly. But “the pure in heart shall see God,”[710] when they arrive at the final perfection. For since the soul became too enfeebled for the apprehension of realities, we needed a divine teacher. The Saviour is sent down—a teacher and leader in the acquisition of the good—the secret and sacred token of the great Providence. “Where, then, is the scribe? where is the searcher of this world? Hath not God made foolish the wisdom of this world?”[711] it is said. And again, “I will destroy the wisdom of the wise, and bring to nothing the understanding of the prudent,”[712] plainly of those wise in their own eyes, and disputatious. Excellently therefore Jeremiah says, “Thus saith the Lord, Stand in the ways, and ask for the eternal paths, what is the good way, and walk in it, and ye shall find expiation for your souls.”[713] Ask, he says, and inquire of those who know, without contention and dispute. And on learning the way of truth, let us walk on the right way, without turning till we attain to what we desire. It was therefore with reason that the king of the Romans (his name was Numa), being a Pythagorean, first of all men, erected a temple to Faith and Peace. “And to Abraham, on believing,

righteousness was reckoned.”[714] He, prosecuting the lofty philosophy of aerial phenomena, and the sublime philosophy of the movements in the heavens, was called Abram, which is interpreted “sublime father.”[715] But afterwards, on looking up to heaven, whether it was that he saw the Son in the spirit, as some explain, or a glorious angel, or in any other way recognised God to be superior to the creation, and all the order in it, he receives in addition the Alpha, the knowledge of the one and only God, and is called Abraam, having, instead of a natural philosopher, become wise, and a lover of God. For it is interpreted, “elect father of sound.” For by sound is the uttered word: the mind is its father; and the mind of the good man is elect. I cannot forbear praising exceedingly the poet of Agrigentum, who celebrates faith as follows:

“Friends, I know, then, that there is truth in the myths Which I will relate. But very difficult to men, And irksome to the mind, is the attempt of faith.”[716]

Wherefore also the apostle exhorts, “that your faith should not be in the wisdom of men,” who profess to persuade, “but in the power of God,”[717] which alone without proofs, by mere faith, is able to save. “For the most approved of those that are reputable knows how to keep watch. And justice will apprehend the forgers and witnesses of lies,” says the Ephesian.[718] For he, having derived his knowledge from the barbarian philosophy, is acquainted with the purification by fire of those who have led bad lives, which the Stoics afterwards called the Conflagration (ἐκπύρωσις), in which also they teach that each will arise exactly as he was, so treating of the resurrection; while Plato says as follows, that the earth at certain periods is purified by fire and water: “There have been many destructions of men in many ways; and there shall be very great ones by fire and water; and others briefer by innumerable causes.” And after a little he adds: “And, in truth, there is a change of the objects which revolve about earth and heaven; and in the course of long periods there is the destruction of the objects on earth by a great conflagration.” Then he subjoins respecting the deluge: “But when,

again, the gods deluge the earth to purify it with water, those on the mountains, herdsmen and shepherds, are saved; those in your cities are carried down by the rivers into the sea.” And we showed in the first Miscellany that the philosophers of the Greeks are called thieves, inasmuch as they have taken without acknowledgment their principal dogmas from Moses and the prophets. To which also we shall add, that the angels who had obtained the superior rank, having sunk into pleasures, told to the women the secrets which had come to their knowledge; while the rest of the angels concealed them, or rather, kept them against the coming of the Lord. Thence emanated the doctrine of providence, and the revelation of high things; and prophecy having already been imparted to the philosophers of the Greeks, the treatment of dogma arose among the philosophers, sometimes true when they hit the mark, and sometimes erroneous, when they comprehended not the secret of the prophetic allegory. And this it is proposed briefly to indicate in running over the points requiring mention. Faith, then, we say, we are to show must not be inert and alone, but accompanied with investigation. For I do not say that we are not to inquire at all. For “Search, and thou shalt find,”[719] it is said.

“What is sought may be captured, But what is neglected escapes,”

according to Sophocles.

The like also says Menander the comic poet:

“All things sought, The wisest say, need anxious thought.”

But we ought to direct the visual faculty of the soul aright to discovery, and to clear away obstacles; and to cast clean away contention, and envy, and strife, destined to perish miserably from among men.

For very beautifully does Timon of Phlius write:

“And Strife, the Plague of Mortals, stalks vainly shrieking, The sister of Murderous Quarrel and Discord, Which rolls blindly over all things. But then It sets its head towards men, and casts them on hope.”

Then a little below he adds:

“For who hath set these to fight in deadly strife? A rabble keeping pace with Echo; for, enraged at those silent, It raised an evil disease against men, and many perished;” of the speech which denies what is false, and of the dilemma, of that which is concealed, of the Sorites, and of the Crocodilean, of that which is open, and of ambiguities and sophisms. To inquire, then, respecting God, if it tend not to strife, but to discovery, is salutary. For it is written in David, “The poor eat, and shall be filled; and they shall praise the Lord that seek Him. Your heart shall live for ever.”[720] For they who seek Him after the true search, praising the Lord, shall be filled with the gift that comes from God, that is, knowledge. And their soul shall live; for the soul is figuratively termed the heart, which ministers life: for by the Son is the Father known.

We ought not to surrender our ears to all who speak and write rashly. For cups also, which are taken hold of by many by the ears, are dirtied, and lose the ears; and besides, when they fall they are broken. In the same way also, those, who have polluted the pure hearing of faith by many trifles, at last becoming deaf to the truth, become useless and fall to the earth. It is not, then, without reason that we commanded boys to kiss their relations, holding them by the ears; indicating this, that the feeling of love is engendered by hearing. And “God,” who is known to those who love, “is love,”[721] as “God,” who by instruction is communicated to the faithful, “is faithful;”[722] and we must be allied to Him by divine love: so that by like we may see like, hearing the word of truth guilelessly and purely, as children who obey us. And this was what he, whoever he

was, indicated who wrote on the entrance to the temple at Epidaurus the inscription:

“Pure he must be who goes within The incense-perfumed fane.”

And purity is “to think holy thoughts.” “Except ye become as these little children, ye shall not enter,” it is said, “into the kingdom of heaven.”[723] For there the temple of God is seen established on three foundations—faith, hope, and love.

CHAPTER II. ON HOPE.

Respecting faith we have adduced sufficient testimonies of writings among the Greeks. But in order not to exceed bounds, through eagerness to collect a very great many also respecting hope and love, suffice it merely to say that in the Crito Socrates, who prefers a good life and death to life itself, thinks that we have hope of another life after death.

Also in the Phædrushe says, “That only when in a separate state can the soul become partaker of the wisdom which is true, and surpasses human power; and when, having reached the end of hope by philosophic love, desire shall waft it to heaven, then,” says he, “does it receive the commencement of another, an immortal life.” And in the Symposium he says, “That there is instilled into all the natural love of generating what is like, and in men of generating men alone, and in the good man of the generation of the counterpart of himself. But it is impossible for the good man to do this without possessing the perfect virtues, in which he will train the youth who have recourse to him.” And as he says in the Theætetus, “He will beget and finish men. For some procreate by the body, others by the soul;” since also with the barbarian philosophers to teach and enlighten is called to regenerate; and “I have begotten you in Jesus Christ,”[724] says the good apostle somewhere.

Empedocles, too, enumerates friendship among the elements, conceiving it as a combining love:

“Which do you look at with your mind; and don’t sit gaping with your eyes.”

Parmenides, too, in his poem, alluding to hope, speaks thus:

“Yet look with the mind certainly on what is absent as present, For it will not sever that which is from the grasp it has of that which is Not, even if scattered in every direction over the world or combined.”

CHAPTER III.

THE OBJECTS OF FAITH AND HOPE PERCEIVED BY THE MIND ALONE.

For he who hopes, as he who believes, sees intellectual objects and future things with the mind. If, then, we affirm that aught is just, and affirm it to be good, and we also say that truth is something, yet we have never seen any of such objects with our eyes, but with our mind alone. Now the Word of God says, “I am the truth.”[725] The Word is then to be contemplated by the mind. “Do you aver,” it was said,[726] “that there are any true philosophers?” “Yes,” said I, “those who love to contemplate the truth.” In the Phædrusalso, Plato, speaking of the truth, shows it as an idea. Now an idea is a conception of God; and this the barbarians have termed the Word of God. The words are as follow: “For one must then dare to speak the truth, especially in speaking of the truth. For the essence of the soul, being colourless, formless, and intangible, is visible only to God,[727] its guide.” Now the Word issuing forth was the cause of creation; then also he generated himself, “when the Word had become flesh,”[728] that He might be seen. The righteous man will seek the discovery that flows from love, to which if he hastes he prospers. For it is said, “To him that knocketh, it shall be opened: ask, and it shall be given to you.”[729] “For the violent that storm the kingdom”[730] are not so in disputatious speeches; but by continuance in a right life and unceasing prayers, are said “to take it by force,” wiping away the blots left by their previous sins.

“You may obtain wickedness, even in great abundance.[731] And him who toils God helps; For the gifts of the Muses, hard to win, Lie not before you, for any one to bear away.”

The knowledge of ignorance is, then, the first lesson in walking according to the Word. An ignorant man has sought, and having sought, he finds the teacher; and finding has believed, and believing has hoped; and henceforward having loved, is assimilated to what

was loved—endeavouring to be what he first loved. Such is the method Socrates shows Alcibiades, who thus questions: “Do you not think that I shall know about what is right otherwise?” “Yes, if you have found out.” “But you don’t think I have found out?” “Certainly, if you have sought.” “Then you don’t think that I have sought?” “Yes, if you think you do not know.”[732] So with the lamps of the wise virgins, lighted at night in the great darkness of ignorance, which the Scripture signified by “night.” Wise souls, pure as virgins, understanding themselves to be situated amidst the ignorance of the world, kindle the light, and rouse the mind, and illumine the darkness, and dispel ignorance, and seek truth, and await the appearance of the Teacher.

“The mob, then,” said I, “cannot become a philosopher.”[733]

“Many rod-bearers there are, but few Bacchi,” according to Plato. “For many are called, but few chosen.”[734] “Knowledge is not in all,”[735] says the apostle. “And pray that we may be delivered from unreasonable and wicked men: for all men have not faith.”[736] And the Poeticsof Cleanthes, the Stoic, writes to the following effect:

“Look not to glory, wishing to be suddenly wise, And fear not the undiscerning and rash opinion of the many; For the multitude has not an intelligent, or wise, or right judgment, And it is in few men that you will find this.”[737]

And more sententiously the comic poet briefly says:

“It is a shame to judge of what is right by much noise.”

For they heard, I think, that excellent wisdom, which says to us, “Watch your opportunity in the midst of the foolish, and in the midst of the intelligent continue.”[738] And again, “The wise will conceal sense.”[739] For the many demand demonstration as a pledge of truth, not satisfied with the bare salvation by faith.

“But it is strongly incumbent to disbelieve the dominant wicked, And as is enjoined by the assurance of our muse, Know by dissecting the utterance within your breast.”

“For this is habitual to the wicked,” says Empedocles, “to wish to overbear what is true by disbelieving it.” And that our tenets are probable and worthy of belief, the Greeks shall know, the point being more thoroughly investigated in what follows. For we are taught what is like by what is like. For says Solomon, “Answer a fool according to his folly.”[740] Wherefore also, to those that ask the wisdom that is with us, we are to hold out things suitable, that with the greatest possible ease they may, through their own ideas, be likely to arrive at faith in the truth. For “I became all things to all men, that I might gain all men.”[741] Since also “the rain” of the divine grace is sent down “on the just and the unjust.”[742] “Is He the God of the Jews only, and not also of the Gentiles? Yes, also of the Gentiles: if indeed He is one God,”[743] exclaims the noble apostle.

CHAPTER IV.

DIVINE THINGS WRAPPED UP IN FIGURES BOTH IN THE SACRED AND IN HEATHEN WRITERS.

But since they will believe neither in what is good justly nor in knowledge unto salvation, we ourselves reckoning what they claim as belonging to us, because all things are God’s; and especially since what is good proceeded from us to the Greeks, let us handle those things as they are capable of hearing. For intelligence or rectitude this great crowd estimates not by truth, but by what they are delighted with. And they will be pleased not more with other things than with what is like themselves. For he who is still blind and dumb, not having understanding, or the undazzled and keen vision of the contemplative soul, which the Saviour confers, like the uninitiated at the mysteries, or the unmusical at dances, not being yet pure and worthy of the pure truth, but still discordant and disordered and material, must stand outside of the divine choir. “For we compare spiritual things with spiritual.”[744] Wherefore, in accordance with the method of concealment, the truly sacred Word, truly divine and most necessary for us, deposited in the shrine of truth, was by the Egyptians indicated by what were called among them adyta, and by the Hebrews by the veil. Only the consecrated—that is, those devoted to God, circumcised in the desires of the passions for the sake of love to that which is alone divine—were allowed access to them. For Plato also thought it not lawful for “the impure to touch the pure.”

Thence the prophecies and oracles are spoken in enigmas, and the mysteries are not exhibited incontinently to all and sundry, but only after certain purifications and previous instructions.

“For the Muse was not then Greedy of gain or mercenary; Nor were Terpsichore’s sweet, Honey-toned, silvery soft-voiced Strains made merchandise of.”

Now those instructed among the Egyptians learned first of all that style of the Egyptian letters which is called Epistolographic; and second, the Hieratic, which the sacred scribes practise; and finally, and last of all, the Hieroglyphic, of which one kind which is by the first elements is literal (Kyriologic), and the other Symbolic. Of the Symbolic, one kind speaks literally by imitation, and another writes as it were figuratively; and another is quite allegorical, using certain enigmas.

Wishing to express Sun in writing, they make a circle; and Moon, a figure like the Moon, like its proper shape. But in using the figurative style, by transposing and transferring, by changing and by transforming in many ways as suits them, they draw characters. In relating the praises of the kings in theological myths, they write in anaglyphs.[745] Let the following stand as a specimen of the third species—the Enigmatic. For the rest of the stars, on account of their oblique course, they have figured like the bodies of serpents; but the sun like that of a beetle, because it makes a round figure of oxdung, and rolls it before its face. And they say that this creature lives six months under ground, and the other division of the year above ground, and emits its seed into the ball, and brings forth; and that there is not a female beetle. All then, in a word, who have spoken of divine things, both Barbarians and Greeks, have veiled the first principles of things, and delivered the truth in enigmas, and symbols, and allegories, and metaphors, and such like tropes. Such also are the oracles among the Greeks. And the Pythian Apollo is called Loxias. Also the maxims of those among the Greeks called wise men, in a few sayings indicate the unfolding of matter of considerable importance. Such certainly is that maxim, “Spare Time:” either because life is short, and we ought not to expend this time in vain; or, on the other hand, it bids you spare your personal expenses; so that, though you live many years, necessaries may not fail you. Similarly also the maxim “Knowthyself” shows many things; both that thou art mortal, and that thou wast born a human being; and also that, in comparison with the other excellences of life, thou art of no account, because thou sayest that thou art rich or

renowned; or, on the other hand, that, being rich or renowned, you are not honoured on account of your advantages alone. And it says, Know for what thou wert born, and whose image thou art; and what is thy essence, and what thy creation, and what thy relation to God, and the like. And the Spirit says by Isaiah the prophet, “I will give thee treasures, hidden, dark.”[746] Now wisdom, hard to hunt, is the treasures of God and unfailing riches. But those, taught in theology by those prophets, the poets, philosophize much by way of a hidden sense. I mean Orpheus, Linus, Musæus, Homer, and Hesiod, and those in this fashion wise. The persuasive style of poetry is for them a veil for the many. Dreams and signs are all more or less obscure to men, not from jealousy (for it were wrong to conceive of God as subject to passions), but in order that research, introducing to the understanding of enigmas, may haste to the discovery of truth. Thus Sophocles the tragic poet somewhere says:

“And God I know to be such an one, Ever the revealer of enigmas to the wise, But to the perverse bad, although a teacher in few words,”—

putting bad instead of simple. Expressly then respecting all our Scripture, as if spoken in a parable, it is written in the Psalms, “Hear, O my people, my law: incline your ear to the words of my mouth. I will open my mouth in parables, I will utter my problems from the beginning.”[747] Similarly speaks the noble apostle to the following effect: “Howbeit we speak wisdom among those that are perfect; yet not the wisdom of this world, nor of the princes of this world, that come to nought. But we speak the wisdom of God hidden in a mystery; which none of the princes of this world knew. For had they known it, they would not have crucified the Lord of glory.”[748]

The philosophers did not exert themselves in contemning the appearance of the Lord. It therefore follows that it is the opinion of the wise among the Jews which the apostle inveighs against it. Wherefore he adds, “But we preach, as it is written, what eye hath not seen, and ear hath not heard, and hath not entered into the

heart of man, what God hath prepared for them that love Him. For God hath revealed it to us by the Spirit. For the Spirit searcheth all things, even the deep things of God.”[749] For he recognises the spiritual man and the gnostic as the disciple of the Holy Spirit dispensed by God, which is the mind of Christ. “But the natural man receiveth not the things of the Spirit, for they are foolishness to him.”[750] Now the apostle, in contradistinction to gnostic perfection, calls the common faith thefoundation, and sometimes milk, writing on this wise: “Brethren, I could not speak to you as to spiritual, but as to carnal, to babes in Christ. I have fed you with milk, not with meat: for ye were not able. Neither yet are ye now able. For ye are yet carnal: for whereas there is among you envy and strife, are ye not carnal, and walk as men?”[751] Which things are the choice of those men who are sinners. But those who abstain from these things give their thoughts to divine things, and partake of gnostic food. “According to the grace,” it is said, “given to me as a wise master builder, I have laid the foundation. And another buildeth on it gold and silver, precious stones.”[752] Such is the gnostic superstructure on the foundation of faith in Christ Jesus. But “the stubble, and the wood, and the hay,” are the additions of heresies. “But the fire shall try every man’s work, of what sort it is.” In allusion to the gnostic edifice also in the Epistle to the Romans, he says, “For I desire to see you, that I may impart unto you a spiritual gift, that ye may be established.”[753] It was impossible that gifts of this sort could be written without disguise.

CHAPTER V. ON THE SYMBOLS OF PYTHAGORAS.

Now the Pythagorean symbols were connected with the Barbarian philosophy in the most recondite way. For instance, the Samian counsels “not to have a swallow in the house;” that is, not to receive a loquacious, whispering, garrulous man, who cannot contain what has been communicated to him. “For the swallow, and the turtle, and the sparrows of the field, know the times of their entrance,”[754] says the Scripture; and one ought never to dwell with trifles. And the turtle-dove murmuring shows the thankless slander of fault-finding, and is rightly expelled the house.

“Don’t mutter against me, sitting by one in one place, another in another.”[755]

The swallow too, which suggests the fable of Pandion, seeing it is right to detest the incidents reported of it, some of which we hear Tereus suffered, and some of which he inflicted. It pursues also the musical grasshoppers, whence he who is a persecutor of the word ought to be driven away.

“By sceptre-bearing Here, whose eye surveys Olympus, I have a trusty closet for tongues,” says Poetry. Æschylus also says:

“But I, too, have a key as a guard on my tongue.”

Again Pythagoras commanded, “When the pot is lifted off the fire, not to leave its mark in the ashes, but to scatter them;” and “people on getting up from bed, to shake the bed-clothes.” For he intimated that it was necessary not only to efface the mark, but not to leave even a trace of anger; and that on its ceasing to boil, it was to be composed, and all memory of injury to be wiped out. “And let not the sun,” says the Scripture, “go down upon your wrath.”[756] And

he that said, “Thou shalt not desire,”[757] took away all memory of wrong; for wrath is found to be the impulse of concupiscence in a mild soul, especially seeking irrational revenge. In the same way “the bed is ordered to be shaken up,” so that there may be no recollection of effusion in sleep, or sleep in the day-time; nor, besides, of pleasure during the night. And he intimated that the vision of the dark ought to be dissipated speedily by the light of truth. “Be angry, and sin not,” says David, teaching us that we ought not to assent to the impression, and not to follow it up by action, and so confirm wrath.

Again, “Don’t sail on land” is a Pythagorean saying, and shows that taxes and similar contracts, being troublesome and fluctuating, ought to be declined. Wherefore also the Word says that the taxgatherers shall be saved with difficulty.[758]

And again, “Don’t wear a ring, nor engrave on it the images of the gods,” enjoins Pythagoras; as Moses ages before enacted expressly, that neither a graven, nor molten, nor moulded, nor painted likeness should be made; so that we may not cleave to things of sense, but pass to intellectual objects: for familiarity with the sight disparages the reverence of what is divine; and to worship that which is immaterial by matter, is to dishonour it by sense. Wherefore the wisest of the Egyptian priests decided that the temple of Athene should be hypæthral, just as the Hebrews constructed the temple without an image. And some, in worshipping God, make a representation of heaven containing the stars; and so worship, although Scripture says, “Let us make man in our image and likeness.”[759] I think it worth while also to adduce the utterance of Eurysus the Pythagorean, which is as follows, who in his book On Fortune, having said that the “Creator, on making man, took Himself as an exemplar,” added, “And the body is like the other things, as being made of the same material, and fashioned by the best workman, who wrought it, taking Himself as the archetype.” And, in fine, Pythagoras and his followers, with Plato also, and most of the other philosophers, were best acquainted with the Lawgiver, as may

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